Supernucleophilic 4 - substituted-pyridine catalysts, and processes useful for preparing same

ABSTRACT

Described are preferred processes for producing extrusion-granulated supernucleophilic 4-amino-substituted pyridine catalysts, and granular products obtainable thereform. Also described are preferred activation-substitution-deactivation processes for producing 4-aminopyridine compounds, which involve the use of acrylic acid or acrylamide or analogs thereof for activation, and substitution steps conducted under mild basic conditions in an excess of the amine reagent for 4-substitution. Such processes provide improved reacted masses which are more readily processed to recover the products in pure, heat-stable form. Further, described are processes for preparing 4-substituted-pyridines via pyridine betaines.

REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority upon U.S. patent applicationSer. No. 60/055,086 filed Aug. 1, 1997 and U.S. patent application Ser.No. 60/054,473 filed Aug. 1, 1997, each of which is hereby incorporatedby reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] The present invention resides generally in the field of thepreparation and use of 4-substituted pyridine compounds, and inparticular to novel forms of supernucleophilic 4-substituted pyridinecatalysts, and nucleophilic substitution processes useful for preparingsuch catalysts and other 4-substituted pyridines.

[0003] As further background, it is well known that many pyridinescarrying an amino (desirably tertiary amino) group at the 4-positionpossess supernucleophilic properties making them highly advantageous foruse as catalysts in acylation and other reactions. For example, thecompound 4-N,N-dimethylaminopyridine (DMAP) is used on a large scaleworldwide for acylation and other reactions in the pharmaceutical andagricultural industries. Historically, the preparation of 4-substitutedpyridines such as DMAP has presented several challenges.

[0004] For example, tremendous research efforts worldwide have been madeto discover effective means for transforming one group at the 4-positionof the pyridine ring for another. Early on, researchers were hopefulthat direct exposure of the free pyridine base to appropriate reagentswould result in the effective modification of the 4-position. It hasturned out, however, that most modifications of interest at the4-position occur only at the cost of extreme conditions. For instance,2-bromopyridine can be converted to 2-aminopyridine by reaction withammonium hydroxide, but only at high temperatures of 200° C. and underpressure. Den Hertog et al., Rec. Trav. Chim., 51, 381 (1932).Similarly, dimethylamine reacts with 4-chloropyridine only underpressure and at a temperature of 150° C. (L. Pentimalli, Gass. Chem.Ital., 94, 902 (1964)), a process unsuitable for commercial scale.Likewise unsuitable for commercial scale is the reaction of sodium orpotassium amide and metal methylanilides in etheral solvents or liquidammonia, as described in Hauser, J. Org. Chem., 15, 310 (1949).N-pyridyl-4-pyridinium chloride hydrochloride or 4-phenoxypyridine hasbeen reacted with nucleophiles to displace at the 4-position (D. Jerchelet al., Chem. Ber., 91, 1266 (1958)). However, these starting pyridinematerials are far removed from commerce and thus such processes would beproblematic if contemplated on a large scale.

[0005] In light of the difficulties of 4-substitution directly on thefree base pyridine, a number of processes have been developed in whichthe 4-position (or 2-position) of the pyridine ring is activated towardnucleophilic substitution by a modification of the ring nitrogen of thepyridine. Such processes are generally known asactivation-substitution-deactivation processes, and to date haveinvolved either the N-oxidation or quaternization of the pyridinesubstrate, both of which are known to activate the 2- and 4-ringpositions toward nucleophilic attack and expulsion of leaving groups atthese positions. N-oxidation as a means to activate the 2- and 4-ringpositions of pyridine has been relatively less studied thanquaternization. This may be due to the fact that the level of activationimparted by N-oxidation is lower than that of quaternization. In thelatter field, it is known that 4-substituted-pyridines such as4-cyanopyridine can be quaternized with an alkyl iodide (e.g. methyliodide) and reacted with ammonia to form a corresponding4-aminopyridine. Metzger et al., J. Org. Chem., 41 (15), 2621 (1978).The dequaternization of such alkyl quats, however, is problematic, asonly relatively exotic reagents such astriphenylphosphene/dimethylformamide (Aumann et al., J. Chem. Soc. Chem.Commun., 32, (1973)), triphenylphosphene/acetonitrile (Kutney et al.,Synth. Commun., 5 (2), 119 (1975)) anddiazabicyclononane/dimethylformamide or thiourea (Ho, Synth. Commun., 3,99 (1973)) having been reported, with each of these processes invitingsignificant difficulty on an industrial scale.

[0006] More recently, research efforts have yielded quaternary-activated4-substitution processes which can be practiced with greater advantageon a commercial scale. For example, U.S. Pat. No. 4,158,093 to Bailey etal. describes a route in which a 4-substituted pyridine base isquaternized with 2- or 4-vinylpyridine in the presence of a strong acidto yield a pyridylethyl quaternary salt. This activated quat form canthen be subjected to nucleophilic substitution at the 4-position, andsubsequently dequaternized in the presence of caustic.

[0007] U.S. Pat. Nos. 4,672,121 and 4,772,713 both to Nummy describeprocesses in which the 4-substituted pyridine base is reacted withacrylamide or an alkylacrylamide as the quaternizing reagent, and theresulting carbamoyl quat or a derivative therefrom is subject tonucleophilic displacement at the 4-position, again followed bydequaternization. In these '121 and '713 patents, the quaternization isconducted in the presence of a strong acid, and the substitution anddequaternization are conducted in the presence of a strong base such asalkali metal hydroxides or carbonates, or strong amidine bases.

[0008] The above-described research efforts have culminated in the pastdecade-and-a-half in the successful commercialization and worldwide useof the supernucleophilic catalyst, DMAP, and have opened the door toroutes to similar useful 4-substituted pyridine compounds. However,needs remain for novel and improved 4-substitution processes forpyridines, and improved product forms. Desirable processes would entailthe use of readily-available starting materials and reagents whileproviding high purity products and minimizing and/or simplifyingpurification steps. Improved processes would also minimize reagent useand the need to recycle materials or handle or dispose hazardous wastes.As well, new product forms, especially of supernucleophilic4-substituted pyridine catalysts, would avoid or reduce difficultieswhich have been encountered in the handling of crystalline or flakedcatalyst forms which have been available to date. The present inventionprovides several embodiments, each of which addresses one or more ofthese needs.

SUMMARY OF THE INVENTION

[0009] Accordingly, one feature of the present invention is theprovision of a supernucleophilic 4-substituted pyridine catalyst in aunique form, and a process for making the same. The preferred processfor preparing a granular supernucleophilic 4-substituted pyridinecatalyst, especially a monoalkylamino- or dialkylaminopyridine catalyst,includes a step of providing the supernucleophilic catalyst as a moltenflowable mass. This flowable mass is then extruded through an orificeinto discrete liquid portions each corresponding to a granule to beformed. These liquid portions, in turn, are cooled to form a granularsupernucleophilic catalyst. The granular supernucleophilic catalyst,most preferably 4-N,N-dimethylaminopyridine (DMAP), desirably has anaverage particular diameter of about 1 to about 10 mm. Suitable melttemperatures range from the melting point for the catalyst, e.g.111-112° C. or DMAP, up to just below the decomposition temperature forthe catalyst, with preferred melt temperatures ranging from about themelting point of the catalyst up to about 50° above that point, e.g. forDMAP about 112° C. to about 160° C., more preferably from the meltingpoint up to about 30° C. above the melting point, and especially forDMAP about 115° C. to about 130° C.

[0010] In still more preferred processes, the extruding step isconducted using equipment optimally designed for forming the discreetportions. For example, such may involve an extrusion apparatus equippedto deliver the flowable mass through an orifice for a predeterminedperiod of time to provide drops of the appropriate size. This controlcan be achieved, for example, by providing first and second wall memberseach having orifices, wherein the wall members are movable relative toone another to periodically align orifices in the first member withthose in the second member for the predetermined period of time. Theflowable mass is pressurized against the first wall member such thatwhen the orifices in the first and second wall member are aligned, anamount of the flowable mass is extruded through the aligned orifices,for example downwardly onto a conveyor belt. Most preferred devices forthese purposes include as the first member, a first container, e.g. adrum, filled and pressurized with the flowable mass, and as the secondmember a second container, e.g. a second drum, encasing the firstcontainer. Each container has orifices, and they are movable (e.g.rotatable) with respect to one another (preferably provided by a staticinner container and a movable (rotating) outer container. Movement ofthe second container results in periodic alignment of the orifices forthe predetermined time, during which the drops of supernucleophiliccatalyst material are extruded through the aligned orifices anddownwardly onto a passing conveyer. Such processes provide preferred,smooth-surfaced supernucleophilic catalyst granules of uniform size andshape, for example generally hemispherical in shape.

[0011] Another preferred embodiment of the invention provides a catalystcomposition comprising a granulated supernucleophilic 4-(secondary ortertiary)aminopyridine catalyst, especially a dialkylaminopyridinecatalyst such as DMAP. Preferred such catalysts have an average particlediameter of about 1 mm to about 10 mm, with most preferred catalystforms having smooth granules of substantially uniform size and/or shape.

[0012] Additional preferred embodiments of the invention relate toimproved activation-substitution-deactivation routes to 4-substitutedpyridines. On such preferred embodiment involves a process for preparinga 4-(secondary or tertiary)aminopyridine compound. This process includesreacting a starting 4-substituted pyridine base having a leaving groupas the 4-substituent, with an activating agent of the formula:

[0013] wherein R³ and R⁴, which may be the same as or may differ fromone another, are each —H or a C₁-C₄ alkyl group, and Z is —OR⁷ orNR⁵R^(6,) wherein R⁵ and R⁶, which may be the same as or may differ fromone another, and may taken together form a ring, are each —H or C₁-C₈alkyl; and R⁷ is —H or C₁-C₈ alkyl. This reacting forms an activated1,4-substituted pyridine, which is then reacted with a primary orsecondary amine in at least a 3:1 molar ratio relative to the pyridine,to form a corresponding 1-substituted,4-(secondary ortertiary)aminopyridine. The 1-substituted, 4-(secondary ortertiary)aminopyridine is then treated to remove the 1-substituent andthereby form a product medium including the 4-(secondary ortertiary)aminopyridine. It has been found that by conducting thesubstitution step in the presence of a large molar excess of the amineused as the nucleophile in the substitution, the use of strong basessuch as alkali metal hydroxides in the substitution step can beminimized or eliminated, and that downstream product separations aresimplified, providing highly pure, white 4-(secondary or tertiary)aminopyridine products even absent a solvent recrystallization step.This process is applied with preference to a manufacture of DMAP,wherein the amine is dimethylamine. The activating agent in this processis preferably acrylic acid or acrylamide.

[0014] Another embodiment of the present invention provides anactivation-substitution-deactivation route to 4-nucleophile-substitutedpyridines, wherein the activated pyridine species is a pyridine betaine.Preferred processes include reacting a starting 4-substituted pyridinebase having a leaving group as the 4-substituent, with anα,β-unsaturated acid of the formula

[0015] wherein R³ and R⁴, which may be the same as or may differ fromone another, are each —H or a C₁-C₄ alkyl group, so as to form acorresponding activated 1,4-substituted pyridine betaine. The betaine isreacted with a nucleophile (Nu) to displace the leaving group and form a1-substituted,4-Nu-pyridine betaine. This betaine is then treated toremove the 1-substituent from the 4-Nu-pyridine compound. Preferredprocesses of this embodiment involve activation steps conducted in theabsence of acid other than the α,β-unsaturated acid, and further thenucleophilic substitution is optionally conducted under mild basicconditions (i.e. in the absence of strong bases such as alkali metalhydroxide) in the presence of a primary or secondary amine used as thenucleophile in at least a 3:1 molar ratio relative to the pyridinebetaine. In its most desirable form to date, this process involves thereaction of 4-cyanopyridine with acrylic acid to form a correspondingbetaine. This betaine is reacted with dimethylamine to form acorresponding 4-N,N-dimethylaminopyridine betaine. This betaine is thentreated in the presence of a strong base such as sodium hydroxide toremove the 1-substituent and form DMAP.

[0016] A still further embodiment of the invention provides a novel,optionally isolated, pyridine betaine of the formula

[0017] wherein:

[0018] G is a group selected from —CN and —NR¹R², wherein R¹ and R²,which may be the same or may differ from one another, are each —H or ahydrocarbon group having from one to about ten carbon atoms, especiallyC₁-C₁₀ alkyl groups, and most preferably methyl groups; and

[0019] R³ and R⁴, which may be the same as or may differ from oneanother, are selected from —H and C₁-C₄ alkyl groups.

[0020] A still further preferred embodiment of the invention providesheat stable 4-(secondary or tertiary)aminopyridine catalysts which maybe produced by processes of the invention. Such heat stability can beexhibited in one or more of several ways. For example, preferredproducts, especially DMAP products, have an APHA color of less thanabout 50 and exhibit an increase in APHA color of no greater than about50 when heated in a nitrogen atmosphere at about 120° C. for about 24hours. For instance, more preferred DMAP products have an APHA color ofless than about 10, and exhibit an APHA color of no greater than about50 after heating in a nitrogen atmosphere at about 120° C. for about 24hours. In another feature demonstrating heat stability, the presentinvention provides amorphous (i.e. non-crystalline form) 4-(secondary ortertiary)aminopyridine catalysts, particularly DMAP catalysts, having anAPHA color of less than 20, more preferably less than 10.

[0021] The invention provides improved supernucleophilic catalysts andimproved synthetic routes which can be used to prepare such catalystsand other useful substituted pyridines. The novel catalyst formsovercome handling and processing difficulties previously encounteredwith supernucleophilic catalysts, and preferred processes can be used toprovide high yields while employing readily available materials,minimizing the use of reagents, and/or minimizing the difficulty and/ornumber of product purification steps. Additional objects, features andadvantages of the invention will be apparent from the description thatfollows.

BRIEF DESCRIPTION OF THE FIGURES

[0022]FIG. 1 is a graph of APHA color over time demonstrating heatstability of preferred DMAP product of the invention.

[0023]FIG. 2 is enlarged digital image of a photograph of a preferredgranular DMAP catalyst product of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] For the purposes of promoting an understanding of the principlesof the invention, reference will now be made to certain preferredembodiments thereof and specific language will be used to describe thesame. It will nevertheless be understood that no limitation of the scopeof the invention is thereby intended, such alterations, furthermodifications and applications of the principles of the invention asdescribed herein being contemplated as would normally occur to oneskilled in the art to which the invention relates.

[0025] As disclosed above, one preferred embodiment of the presentinvention provides novel forms of supernucleophilic catalysts. The novelforms in accordance with the invention are granular catalysts, and arepreparable by melt extrusion processes which yield discreet liquidportions which upon solidification form smooth granules or prills.

[0026] Melt extrusion processes of the invention preferably involve theextrusion of molten 4-(secondary or tertiary)aminopyridine catalysts.Preferred catalysts for use in the invention thus include those of theformula:

[0027] wherein R¹ and R², which may be the same as or may differ fromone another, are each —H or a hydrocarbon group having from one to aboutten carbon atoms, especially —H or a C₁-C₁₀ alkyl, with the proviso thatat least one of R¹ and R² is a hydrocarbon group such as alkyl. Morepreferred catalysts occur where R¹ and R² are each alkyl, especiallylower (C₁-C₄) alkyl such as methyl. The most preferred catalyst for meltextrusion processing in accordance with the invention is DMAP (i.e., R¹and R² are both methyl).

[0028] As disclosed above, the catalyst is extruded, while molten,through an orifice in a fashion which provides granules of the desiredsize. Processes of the invention can, for example, be conducted in anextrusion apparatus as described in U.S. Pat. No. 4,279,579, which ishereby incorporated herein by reference in its entirety. Such anapparatus includes a first cylindrical container having a plurality oforifices and a second cylindrical container disposed within the firstcontainer and also including a plurality of orifices. Means are providedfor admitting the flowable molten mass of catalyst into the secondcontainer, and means are also provided for producing relative rotationbetween the containers to periodically align the passages of the firstcontainer with the passages of the second container, so as to depositdrops of the flowable mass through the passages downwardly onto aconveyor belt also provided in the apparatus. Such processes in whichdiscreet drops or portions are caused to solidify to form flowablegranules are generally referred to as prilling processes, and theresulting granules are referred to as prills. In the preferred process,the conveyor belt is a cooled stainless steel belt, which hastens thesolidification of the flowable mass drops as they exit the passageprovided by the aligned orifices. Suitable devices for the conduct ofsuch processes are commercially available from Sandvic Process Systems,Inc. of Totowa, N.J., U.S.A. Further information regarding such devicesis available from Sandvic's trade literature, including that entitledSandvik Rotoform® Process, Premium Pastilles at high production rates,low production costs (1993); A World of Chemical Experience in ChemicalProcessing: Sandvik Process Systems.

[0029] As indicated, the supernucleophilic catalyst is provided in amolten state for extrusion processing. Preferred melt processingtemperatures will range from about the melting point of the catalyst upto the decomposition temperature of the catalyst. More Preferredtemperatures will be at about the melting point up to about 50° C. abovethe melting point of the catalyst in hand. For the most preferredcatalyst, DMAP, a generally suitable temperature range is about 112° C.to about 200° C., and a more preferred temperature range is about 115°C. to about 130° C. In any event, the temperature utilized will beselected in light of the conditions at hand, and will be optimized toprovide the desired viscosity of the flowable catalyst mass forextrusion processing in accordance with the invention.

[0030] Granulated catalysts in accordance with the invention willpreferably have smooth granules with an average particle diameter ofabout 1 to about 10 mm, more preferably about 1 to about 5 mm. Inaddition, preferred catalysts will have granules of substantiallyuniform shape and size. When produced by preferred extrusion processesas described above, granulated catalysts of the invention will have asubstantially 3-dimensional shape (i.e. the deposited drops willsolidify prior to their spreading to form a substantially 2-dimensionalflake), which provides improved flow properties for the solid catalystin accordance with the invention. Preferred granules so prepared willgenerally also have a relatively flat or planar surface on a first side(from contact with the conveyor belt), and a generally arcuate surfaceon a second side opposite the first side. Preferred granulated catalystsof the invention also exhibit desirable dissolution properties inaqueous medium, meaning that while provided in a readily handled andmanipulated granulated Form in the dry state, once placed in aqueousmedia, the catalyst granules break up and dissolve into solution withrelative ease and quickness, generally within about a few minutes withagitation at the catalytic levels at which they are conventionally used(e.g. at concentration levels less than about 10% by weight insolution). In addition, preferred granulated products of the inventionwill have a low level of fines having a particle diameter of less than600 microns, more preferably less than 5% by weight fines, and mostpreferably less than 3% by weight fines. Particle integrity of preferredproducts will also minimize the generation of fines under conditions ofabrasion and impact. For example, preferred products will generate lessthan 10% by weight fines in friability testing under test methods S4-77and/or S5-77 as described further in Example 9 below, more preferablyless than 5% by weight generated fines and most preferably less than 2%by weight.

[0031] The preferred granulated catalysts of the invention arefree-flowing, and exhibit little to no tendency to aggregate. Thesecatalysts thus overcome difficulties which have been encountered withprior crystalline or flaked DMAP forms, and are advantageously handledin manufacturing, storage and use operations. As illustrations,catalysts of the invention demonstrate advantages making them wellsuited for transport operations including gravity flow or vacuum,(e.g.as in gravity flow addition or vacuum addition to reactors), and canoptionally be packaged in containers adapted to facilitate suchoperations. For instance, in the case of gravity flow addition,granulated catalysts of the invention can be packaged in containers thatare adapted for connection to reactor ports and that incorporate productrelease mechanisms that are activatable upon or after such connection.Such containers may also be adapted for efficient gravity flow of thegranular catalyst out of an opening of the container, and in this regardmay have a shape adapted to release all of the granular catalyst uponactivation of the product release mechanism. To this end, the containermay include one or more wall members inclined downwardly toward theopening of the container adapted for connection to the reactor port. Inthis manner, safe, efficient and convenient use of granular catalysts ofthe invention is facilitated.

[0032] The supernucleophilic catalyst material for use in preparingadvantageous granules of the invention may be synthesized by anysuitable route. For example, it may be prepared usingactivation-substitution-deactivation techniques described in any one ofU.S. Pat. Nos. 4,158,093, 4,672,121 or 4,772,713, each of which ishereby incorporated by reference in its entirety. The supernucleophiliccatalyst starting material may also be prepared by improved syntheticprocesses of the present invention as described below.

[0033] One preferred process of the invention involvesactivation-substitution-deactivation processes for preparing4-substituted pyridine compounds, wherein the activating agent is anacrylic derivative or analog, and wherein the substitution step isconducted in the presence of a large excess of a secondary or tertiaryamine (HNR¹R² wherein R¹ and R² are defined as above) used as thenucleophile to displace the leaving group during the substitutionreaction.

[0034] Thus, in accordance with this process of the invention, a4-L-substituted pyridine base, wherein L is a leaving group, will firstbe activated by reaction with an activating agent of the formula:

[0035] wherein R³ and R⁴, which may be the same as or may differ fromone another, are each —H or a C₁-C₄ alkyl group, and Z is —NR⁵R⁶ or —OR⁷or, wherein R⁵ and R⁶, which may be the same as or may differ from oneanother, and may taken together form a ring, are each —H or C₁-C₈alkyl;and R⁷ is —H or C₁-C₈ alkyl.

[0036] Advantageous activation reactions will in general employ a molarexcess of the activating agent relative to the pyridine base startingmaterial to facilitate high levels of conversion. Accordingly, molarratios of activating agent to pyridine base starting material willtypically be in the range of 1.05:1 up to about 10:1, respectively, moretypically in the range of about 1.05:1 to about 5:1.In addition, theactivating agent may contain one or more polymerization inhibitors, inorder to prevent unwanted polymerization. For example, thepolymerization inhibitor may be MEAQ or a suitable thiazine compoundsuch as phenylthiazine that is effective to prevent polymerization ofthe activating agents under distillative conditions.

[0037] The activation step is preferably performed in the presence of astrong acid catalyst (pKa less than 3), for example a strong organicacid, or a strong inorganic acid such as HCl, HBr, HI, sulfuric acid orphosphoric acid. Such acids will typically be used in a molar ratio ofabout 1-3:1 relative to the 4-L-substituted pyridine starting material,more preferably in a slight molar excess (e.g. in a molar ratio of about1.05:1) relative to the pyridine starting material. The activationreaction is also preferably conducted under heated conditions, withtemperatures in the range of about 50° C. to about 100° being typical,more preferably in the range of about 70° C. to about 80° C. Theactivation reaction can be conducted for several hours, with about 95%+conversion being achieved in about four hours in more preferredinventive processes.

[0038] The concentration of the reaction during the activation step willvary in accordance with the particular reactants and reagents in hand,and the optimization of this parameter will be well within the skill ofthose practiced in a relevant field. Suitable reaction concentrationswill generally provide reacted solutions containing about 10% to about60% by weight of the activated pyridine intermediate, more typically inthe range of about 30% to about 55% by weight.

[0039] Preferred products of such activation reactions will thus havethe formula:

[0040] wherein:

[0041] Z, R³ and R⁴ are as defined above; and

[0042] A is an anion (provided, e.g., by the anion of the strong acidcatalyst); and

[0043] L is a leaving group such as cyano, halo (fluoro, chloro, bromo,or iodo), arylsulfonyl having from six to ten carbon atoms, optionallysubstituted with one or more alkyl groups having from one to four carbonatoms; arylsulfonyloxy having from six to ten carbon atoms;alkylsulfonyloxy having from one to eight carbon atoms; aryloxy havingfrom six to ten carbon atoms (e.g. phenoxy); arylthio having from six toten carbon atoms (e.g. phenylthio); nitro, and the like.

[0044] In accordance with the invention, the activated 1,4-L-substituted pyridine formed in the activation step is then reactedin the presence of a primary or secondary amine charged n at least abouta 2:1 molar ratio relative to the activated 1,4-substituted pyridineunder mild (pH about 8 to about 10) basic conditions at the completionof combining the activated 1,4-substituted pyridine and the primary orsecondary amine, most preferably at essentially the basic pH provided bythe pyridine and primary or secondary amine reagents, i.e. in thesubstantial absence of any strong base such as sodium hydroxide in thereaction medium. In conducting this reaction, it is generally preferredto add the activated pyridine intermediate to an aqueous solution of theamine nucleophile, as this has been found to provide cleaner processes.Preferred amine nucleophiles for these purposes include those of theformula HNR¹R² wherein R¹ and R² are as defined above. Additionalillustrative amines include hydrazine, alkylene diamines of up to eightcarbon atoms, dialkylenetriamines of up to sixteen carbon atoms,polyethylenimines, and the like.

[0045] In contrast to prior known processes in which sodium hydroxide orsimilar bases have been used, it has been discovered that such stronglybasic conditions can be avoided in the substitution step, and in sodoing that cleaner reacted mediums are provided downstream, which aremore readily processed to recover substantially pure 4-(secondary ortertiary)aminopyridines. More preferred substitution reactions areconducted in the presence of the primary or secondary amine in at leasta 3:1 molar ratio relative to the pyridine compound, typically in abouta 3-5:1 molar ratio. This reaction can be suitably conducted at roomtemperature (about 25° C.) or under heated conditions. For reactions atatmospheric pressure, preferred reaction temperatures will be roomtemperature up co about the boiling temperature for the lowest boilingcomponent of the reaction mixture, typically the primary or secondaryamine. For instance, in the manufacture of DMAP, the substitutionreaction is typically conducted at temperatures of to about 60-70° C.,as higher temperatures would begin to boil off the dimethylamine.

[0046] In the substitution reaction, the primary or secondary aminedisplaces the leaving group “L”, losing a hydrogen atom in the process,so as to form an activated 1-substituted,4-(secondary ortertiary)aminopyridine. The extent of completion of this reaction can bemonitored and the process taken on to the deactivation phase uponachieving sufficient conversion. In the deactivation step, the1-substituted, 4-(secondary or tertiary)aminopyridine is treated toremove the 1-substituent and thereby form a product medium including the4-(secondary or tertiary)aminopyridine, e.g. of the formula:

[0047] wherein R¹ and R² are as defined above.

[0048] As to conditions during the deactivation step, it is preferablyconducted under basic, heated conditions. A strong base such as analkali metal hydroxide can be used to advantage in facilitating theelimination of the 1-substituent. Desirable deactivations are alsoconducted at a temperature in the range of about 80° C. to about 100°C., although higher temperatures and superatmospheric pressures may alsobe employed.

[0049] As indicated above, it has been discovered that by conducting thesubstitution step in the presence of a large molar excess of the amineused as the nucleophile, the use of strong bases such as alkali metalhydroxides in the substitution step can be minimized or eliminated, andthat downstream product separations are simplified, providing highlypure 4-(secondary or tertiary)aminopyridine products. For example, atypical reaction workup to recover the 4-(secondary ortertiary)aminopyridine product will involve an extraction of thereaction medium with a non-polar organic solvent such as toluene, todraw the 4-(secondary or tertiary)aminopyridine product into the organicsolvent layer. The organic layer is then distilled to separate thepyridine product from the organic solvent, with the solvent typicallyhaving a lower boiling point and thus being collected first overhead. Ithas been found, in accordance with the invention, that in processesconducted as described above using mild basic conditions during thesubstitution step, the distillative separation is much cleaner. Thisprovides a distinct separation of the pyridine product, which iscollected overhead immediately as a relatively pure product, as opposedto encountering a need to collect a first, more crude pyridine productfraction, followed by a relatively pure fraction. Moreover, products canbe obtained from such processes which are highly pure, as is exhibitedfor example by the recovery of white DMAP from the distillation step,even absent any subsequent solvent recrystallization. Such whiteproducts readily exhibit APHA colors of less than 50, and demonstratesuperior thermal stability as compared to DMAP products prepared byother processes, as illustrated Example 4 below and its accompanyingFIG. 1. It is thus advantageous to combine such processes withsubsequent melt-processing of the product, without the need for anyintervening crystallization. Suitable melt processing techniquesinclude, for example flaking, or extrusion granulation processes asdescribed above.

[0050] Another aspect of the present invention involves anactivation-substitution-deactivation synthetic route to 4-substitutedpyridines, in which the activated intermediate species is a pyridinebetaine. Generally speaking, these inventive processes involve anactivation step which includes reacting a starting 4-substitutedpyridine base having a leaving group as the 4-substituent, with anα,β-unsaturated acid of the formula

[0051] wherein R³ and R⁴, which may be the same as or may differ fromone another, are each —H or a C₁-C₄ alkyl group, so as to form acorresponding activated 1,4-substituted pyridine betaine. The betaine isreacted with a nucleophilic agent (Nu-H) to displace the leaving groupand form a 1-substituted, 4-Nu-pyridine betaine. This betaine is thentreated to remove the 1-substituent and form the 4-Nu-pyridine compound.

[0052] The activation steps of such processes are conducted in a mediumessentially free from acids other than the α,β-unsaturated acid, so asto enable the formation of the betaine intermediate as opposed to aquaternary salt intermediate incorporating a separate counterioncoordinated with the positively-charged pyridine ring nitrogen. Theactivation steps are desirably conducted in a molar excess of theα,β-unsaturated acid to facilitate high and more rapid conversion of thepyridine base starting material to the betaine intermediate. Suitablemolar ratios of α,β-unsaturated acid to pyridine base are about 1-5:1,respectively, with preferred ratios being about 1.1-3:1, respectively.These reactions are conducted with preference under heated conditions,for example at temperatures ranging from about 50° C. to about 100° C.,more typically from about 50° C. to about 80° C.

[0053] Reaction concentrations during the activation step will againvary in accordance with the particular reactants and reagents in hand,and the optimization of this parameter will be well within the purviewof those skilled in the relevant field. Suitable reaction concentrationswill generally provide reacted solutions containing about 10% to about50% of the activated pyridine intermediate, more typically in the rangeof about 30% to about 40% by weight.

[0054] The nucleophilic substitution reaction can be conducted inconventional fashion, e.g. in the presence of the nucleophilic reagentand added strong base. In so doing, it will generally be possible to useless strong base than in prior-known synthetic routes due to the absenceof strong acid in the reaction medium residual from the activation step.Where the nucleophilic agent is itself basic (e.g. where it is a primaryor secondary amine), as in above-described processes, the nucleophilicsubstitution step is desirably conducted under mild basic conditions(i.e. in the absence of strong bases such as alkali metal hydroxide) inthe presence of the primary or secondary amine in at least a 2:1 molarratio relative to the pyridine betaine, more preferably at least a 3:1molar ratio, typically 3-5:1. As before, this substitution reaction canbe suitably conducted at room temperature (about 25° C.) or under heatedconditions.

[0055] The extent of completion of the substitution reaction can bemonitored and the process taken on to the deactivation step uponachieving sufficient conversion to the 1-substituted,4-Nu-pyridineintermediate. In the deactivation step, the 1-substituted, 4-(secondaryor tertiary)aminopyridine is treated to remove the 1-substituent andthereby form a product medium including the 4-(secondary or tertiary)aminopyridine.

[0056] The deactivation step is preferably conducted under basic, heatedconditions. As before, a strong base such as an alkali metal hydroxideand heat (e.g. about 50° C. to about 100° C.) can be used to advantagein facilitating the elimination of the 1-substituent to form the target4-Nu-pyridine compound.

[0057] Illustrative processes of this embodiment of the inventionutilize 4-substituted pyridine starting materials encompassed by theformula:

[0058] wherein L is a leaving group such as cyano, halo (fluoro, chloro,bromo, or iodo), arylsulfonyl having from six to ten carbon atoms,optionally substituted with one or more alkyl groups having from one tofour carbon atoms; arylsulfonyloxy having from six to ten carbon atoms;alkylsulfonyloxy having from one to eight carbon atoms; aryloxy havingfrom six to ten carbon atoms (e.g. phenoxy); arylthio having from six toten carbon atoms (e.g. phenylthio); nitro, and the like. This startingpyridine is reacted as described above with the α,β-unsaturated acid toform a pyridine betaine intermediate of the formula:

[0059] wherein L, R³ and R⁴ are as defined above. This betaine is thensubjected to a nucleophilic substitution reaction with a nucleophilicreagent, Nu-H, of sufficient strength to displace the leaving group, L,and form a second pyridine betaine intermediate of the formula:

[0060] In turn, this intermediate is treated to remove the1-substituent, e.g. in the presence of caustic and heat, to form a4-substituted pyridine product of the formula:

[0061] More preferred processes of this embodiment of the invention areprovided where L is cyano, the nucleophile is HNR¹R² wherein R¹ and R²are as defined above, resulting in a 4-substituted pyridine product ofthe formula:

[0062] wherein R¹ and R² are as defined above. These processes provideclean distillative separations to recover highly pure 4-substitutedpyridines, which can be taken on to melt processing (e.g. flaking ormelt extrusion as described above) without interveningrecrystallization, to provide high quality product forms.

[0063] In its most desirable form to date, this betaine-mediated processinvolves the reaction of 4-cyanopyridine with acrylic acid to form acorresponding pyridine betaine. This betaine is reacted withdimethylamine to form a corresponding 4-N,N-dimethylaminopyridinebetaine. This betaine is then treated in the presence of a strong basesuch as sodium hydroxide to remove the 1-substituent and form DMAP. Sucha process is illustrated in Scheme 1 below:

[0064] These processes provide substantial savings in reagents due tothe absence of strong acid in the activation step, and the consequentreduced requirements for base during the substitution and/ordequaternization steps. In addition, DMAP products produced by suchbetaine-mediated processes are highly white as recovered fromextraction/distillation steps as described above, and provideadvantageous melt-processed processed product forms readily having APHAcolors of less than about 50.

[0065] Activation-substitution-deactivation processes of the inventionas discussed-above can be conducted for example in batch or continuousmodes. In continuous modes, the processes may occur in continuousstirred tank reactors, tube reactors, or the like. In one preferredform, three continuous reaction zones can be established to carry outthe activation, substitution, and deactivation steps, respectively. Forexample, tube reactors may be utilized wherein the 4-L-substitutedpyridine starting material, especially 4-cyanopryridine, activatingagent, and optionally strong acid such as HCl are combined in a tubereactor and allowed to react to form the 4-L-substituted quat or betaineintermediate. In another continuous zone, e.g. in another tube reactor,the nucleophile (Nu) to substitute for the 4-L-substituent can becombined with the intermediate, and the reaction to form the4-Nu-substituted intermediate caused to proceed. In a still furtherzone, e.g. a still further tube reactor, a base (e.g. aqueous alkali oralkaline earth metal hydroxide such as NaOH) can be combined with thestream containing the 4-Nu-substituted intermediate to deactivate theintermediate and form the desired 4-Nu-substituted pyridine compound.Heat exchangers can also be used to control the heat of the reactantsin, after or between the zones. For example, heat exchangers can beincluded to add heat between the activation and substitution zonesand/or between the substitution and deactivation zones. Still further,continuous recovery operations can be performed to recover the productas it exits the continuous reaction zones. For instance, a continuousextractor can be incorporated into the continuous processing after the4-Nu-pyridine product has been formed, to extract the product from theaqueous chase present into an organic phase. In most preferredcontinuous processes, the product is DMAP, the 4-L-substituted pyridineis 4-cyanopyridine, and the nucleophile is dimethylamine.

[0066] For purposes of promoting a further understanding of the presentinvention and its advantages, the following specific Examples areprovided. It will be understood that these Examples are illustrative,and not limiting, of the present invention.

EXAMPLE 1 Production of 4-Dimethylaminopyridine via Acrylic Acid Quat

[0067] 4-Cyanopyridine (300 gm, 2.882 mole) and 32% aqueous hydrochloricacid (342.3 gm, 3.024 mole) were combined and 50% aqueous acrylic acid(415.2 gm, 2.881 mole) added to the mixture with stirring. The combinedreactants were heated with stirring for four (4) hours at 70° C. Theresulting reacted mixture was then added to a 40% aqueous solution ofdimethylamine (893.6 gm, 995 ml, 7.929 mole) with continued heating andstirring for one (1) hour at 40° C. Fifty percent (50%) aqueous sodiumhydroxide (923.5 gm. 620 ml) was added to the reaction mixture withcontinued stirring and the temperature increased and maintained at 90°C. for one (1) hour. The reaction mixture was cooled to 70° C. andextracted with toluene (150 ml). After separation of layers, the aqueouslayer was extracted with a second portion of toluene (100 ml). Thetoluene layers were combined and distilled. Toluene was removed atatmospheric temperature and 4-dimethylaminopyridine distilled at reducedpressure (b.p. 190° C., 150 mmhg) to give 4-dimethylaminopyridine (299.3gm, 2.4497 mole).

EXAMPLE 2 Production of 4-Dimethylaminopyridine via Acrylic Acid Betaine

[0068] A. Betaine Synthesis

[0069] A one liter, four neck flask was equipped with a mechanicalstirrer, thermometer, and a reflux condenser. The flask was charged with4-cyanopyridine (150.0 g, 1.441 mole), water (360.0 g), and acrylic acid(166.2 g, 2.306 mole). The reaction mixture was heated to 70-75° C. andheld for 5 to 8 hours. Reaction mixtures were then allowed to cool toroom temperature and stirred overnight, or in some cases, over a weekendbefore analysis by NMR. The conversion was determined by ratioing thering protons of the betaine with those of unreacted 4-cyanopyridine, thelimiting reagent.

[0070] B. DMAP Synthesis

[0071] A two liter, four neck flask was equipped with a mechanicalstirrer, reflux condenser, thermometer, and an addition funnel. Theflask was charged with 40% dimethylamine solution (488.2 g, 4.331 mole).With good agitation, the above betaine solution (673.3 g) was added tothe DMA allowing the reaction temperature to reach 45° C. max. Thereaction mixture was stirred for about 15 minutes. The reaction mixturewas then heated to about 70° C. and 50% NaOH (576.8 g, 7.21 mole) wasslowly added. As the NaOH was added, DMA was evolved from the condenserand the temperature was held to 70-80° C. Upon completion of the NaOHaddition, the reaction mixture was heated to reflux and held for onehour to spring the betaine. Alternatively, the DMAP betaine solution, atabout 45° C., has been placed under reduced pressure (water aspirator)and the NaOH was slowly added at the lower temperature. After the NaOHaddition was complete, the reaction mixture was heated to 70° C., whilestill under vacuum, to remove the DMA. At 70° C., the vacuum wasreleased and the reaction mixture heated to reflux and held for 1 to 2hours. The hot reaction mixture, regardless of which method of DMAremoval was used, was cooled to about 90° C. and extracted with toluene(2×150 ml) at 70-80° C. The layers were separated and the top layers(401.4 g) were combined for distillation. The toluene was removed byatmospheric distillation until the pot temperature was 180° C. The potwas slowly eased under vacuum to a pressure of about 110 mm Hg. The DMAPwas distilled at a head temperature of about 185-190° C. until the potwas essentially dry. The DMAP distillate (136.0 g, 1.,113 mole)represented a 77.3% yield. The distillate was crystallized from tolueneas a 40 wt % solution. The crystallized product was recovered using alab centrifuge and dried in a vacuum oven. The dried material (118.1g,0.967 mole) represented a 67.1% yield of crystallized material.

EXAMPLE 3 Production of 4-Dimethylaminopyridine via Acrylamide Quat

[0072] 4-Cyanopyridine (300 gm, 2.882 mole) and 32% aqueous hydrochloricacid (342.3 gm, 3.024 mole) are combined and 50% aqueous acrylamide(2.881 mole) added to the mixture with stirring. The confined reactantsare heated with stirring for four (4) hours at 70° C. A 40% aqueoussolution of dimethylamine (893.6 gm, 995 ml, 7.929 mole) is added to themixture with continued heating and stirring for one (1) hour at 40° C.Fifty percent (50%) aqueous sodium hydroxide (923.5 gm. 620 ml) is addedto the reaction mixture with continued stirring and the temperatureincreased and maintained at 90° C. or one (1) hour. The reaction mixtureis cooled to 70° C. and extracted with toluene (150 ml). Afterseparation of layers, the aqueous layer is extracted with a secondportion of toluene (100 ml). The toluene layers are combined anddistilled. Toluene is removed at atmospheric temperature and4-dimethylaminopyridine distilled at reduced pressure (b.p. 190° C., 150mmhg) to give DMAP.

EXAMPLE 4 Heat Stability Studies for DMAP

[0073] In this Example, a DMAP sample was produced essentially asdescribed in Example 1 hereof. The sample was heated to 120-130° C.,under nitrogen, and held for three days. Samples were taken on a dailybasis to test for color degradation. The results are shown in FIG. 1. Ascan be seen, the product of Example 1 hereof had superior heatstability, having an APHA color of only 50 after 24 hours and of onlyabout 150 after three days under these molten conditions.

[0074] Similar testing of the product of Example 3 hereof reveals thatit also possesses superior heat stability properties.

EXAMPLE 5 Preparation of Melt-Extruded DMAP Granules

[0075] A sample of 4-dimethylaminopyridine was molten, at a temperatureof 115-125° C. The molten material was deposited dropwise onto a smooth,porcelain surface. The drops solidified rapidly and formed granuleswhich were generally hemispherical in shape. The granulated product wasremoved from the surface and charged to a glass container (leavingsubstantial head space) and observed for particle integrity and flowproperties. Upon agitation of the container it was found that thegranules were resistant to fracture and highly free-flowing, exhibitinglittle or no tendency to adhere to one another.

EXAMPLE 6 Automated Melt-Extrusion of DMAP Granules

[0076] 4-N,N-Dimethylaminopyridine (DMAP) is produced as described inExample 1. The 4-N,N-dimethylaminopyridine distillate is maintained inthe molten state and is processed as follows (withoutrecrystallization). The molten DMAP distillate is maintained in astorage tank under a nitrogen atmosphere. The storage tank is connectedas feed to a melt extrusion apparatus, e.g., such as one available fromSandvik Process Systems, Inc., Totowa, N.J., USA, and/or described inU.S. Pat. No. 4,279,579. The apparatus includes a rotating drum withorifices through which the molten product is extruded into discreteliquid portions downwardly onto a moving, cooled stainless steelconveyor belt. The speed and direction of the belt are synchronized withthe linearized speed and direction of the orifices of the rotating drum,to provide efficient and uniform deposit of the molten material onto thebelt.. The extrusion orifices are approximately 1 mm in diameter,leading to approximately 2 to 5 mm diameter granules. The melt extrusionapparatus is operated with the DMAP at a temperature of approximately120-130° C., and the DMAP is preferably maintained at this temperaturethrough storage and extrusion processing or no longer than about 8hours. The resulting, generally hemispherical DMAP granules have goodcolor (APHA color of about 100 or less), are hard, and have smoothsurfaces. The granules are resistant to fracture and have substantialnon-caking properties.

EXAMPLE 7 Automated Melt-Extrusion of DMAP Granules

[0077] The process of Example 6 is repeated, except that the4-dimethylaminopyridine used is prepared via the acrylamide routedescribed in Example 3. Again, the product granules have good color,integrity, and flow properties.

EXAMPLE 8 Automated Melt-Extrusion of DMAP Granules

[0078] In this example a Rotoformer available from Sandvik ProcessSystems, Inc., Totowa, N.J., USA, was used to prepare melt-extruded DMAPgranules (prilled form). This machine generally has the featuresdescribed U.S. Pat. No. 4,279,579, and is also described in SandvikRotoform® Process, Premium Pastilles at high production rates, lowproduction costs (1993); A World of Chemical Experience in ChemicalProcessing: Sandvik Process Systems.

[0079] The bore size on the rotating shell of the rotoformer was 1.5mil. DMAP, prepared generally as described in Example 1, was maintainedas a melt at about 120° C.-140° C. for feed to the rotoformer. Duringoperation of the machine, molten DMAP was extruded through the boresonto the cooled belt of the rotoformer, providing DMAP prills havingdiameters of about 1-4 mil. The prills were removed at the end of thebelt by a micarta laminated plastic blade, at which point the prillsexhibited a temperature of about 30° C. A digital image of a photographof representative DMAP prills is presented as FIG. 2. Upon inspection,the prills were found to be substantially uniform in shape and toexhibit excellent hardness and integrity. The prills also exhibitedlittle or no tendency to cake.

EXAMPLE 9 Friability Testing of DMAP Prills

[0080] DMAP prills prepared as in Example 8 were subjected to friabilitytesting under procedures commonly used to test sulfur and other likeparticulates. In particular, the prills were tested under the proceduresof test methods S4-77 and S5-77. These and other test methods identifiedin this Example were performed as described in Sampling and TestingSulphur Forms, published by the Sulphur Derivatives Institute of Canada,Box 9505 Bloy Valley Square 1, 830-202 Sixth Avenue, Calgary, Alberta,Canada T2P2W6. For the S4-77 method, prilled DMAP samples were ovendried at 50° C. plus or minus 5° C. to constant weight, weighed to thenearest 0.1 and air cooled. The samples were then transferred co atumbler having a diameter of 250 mm and rotated at a speed of 19 rpmplus or minus 1 rpm for a total of 450 revolutions, maintaining asubstantially uniform peripheral speed. After the prescribedrevolutions, the material was cleaned from the tumbler and its weightrecorded. The material was then subjected to dry sieve analysis todetermine particle size distribution. The results are set forth inTable 1. TABLE 1 Original Sample Tumbled Sample Sieve Size PercentRetained Percent Retained μm Individual Cumulative Individual Cumulative4750  0.00  0.00  0.00  0.00 3350  0.12  0.12  0.05  0.05 2360  14.40 14.52  8.50  8.54 2000  48.75  63.27  48.96  57.50 1180  26.05  89.32 29.06  86.56  600  7.64  96.97  10.31  96.87  300  1.68  98.65  2.61 99.48 <300  1.35 100.00  0.52 100.00 Total 100.00 462.87 100.00 449.00Fineness FF_(o) = 4.63 FF_(t) = 4.49 Factor (FF)*

[0081] In the S5-77 test method, a cylindrical tumbler having a diameterof 711 mm and length of 508 mm was used. The tumbler had a 89 mm wideshelf mounted within along the entire length of the cylinder. Thetumbler was rotated 40 times at a speed of 31 rpm plus or minus 1 rpm.The sample was then collected and subjected to dry sieve analysis as inthe S4-77 method discussed above. The results are presented in Table 2.TABLE 2 Original Sample Tumbled Sample Sieve Size Percent RetainedPercent Retained μm Individual Cumulative Individual Cumulative 4750 0.00  0.00  0.00  0.00 3350  0.12  0.12  0.01  0.01 2360  14.40  14.52 7.82  7.83 2000  48.75  63.27  48.40  56.23 1180  26.05  89.32  31.44 87.67  600  7.64  96.97  9.65  97.32  300  1.68  98.65  2.08  99.39<300  1.35 462.87  0.61 100.00 Total 100.00 462.87 100.00 448.44Fineness FF_(o) = 4.63 FF_(t) = 4.48 Factor (FF)*

[0082] The data presented in Tables 1 and 2 demonstrate that the prilledDMAP form not only has a low initial fines content but also exhibitsunexpectedly good particle integrity and resistance to fracture andfines production under conditions of abrasion and impact.

[0083] The invention has been described above in detail, with specificreference to its Preferred embodiments. It will be understood, however,that a variety of modifications and additions can be made to theprocedures disclosed without departing from the spirit and scope of theinvention. Such modifications and additions are desired to be protected.In addition, all publications cited herein are indicative of the levelof skill in the relevant art, and are each hereby incorporated byreference each in their entirety as if individually incorporated byreference and fully set forth.

What is claimed is:
 1. A process for preparing a granularsupernucleophilic 4-(secondary or tertiary)aminopyridine catalyst,comprising: providing the supernucleophilic catalyst as a moltenflowable mass; extruding said molten flowable mass through an orificeinto discrete liquid portions each corresponding to a granule to beformed; and cooling said discrete liquid portions to form the granularsupernucleophilic 4-(secondary or tertiary)aminopyridine catalyst. 2.The process of claim 1, wherein said catalyst is4-N,N-dimethylaminopyridine.
 3. The process of claim 1, wherein saidgranules have an average particle diameter of about 1 to about 10 mm. 4.The process of claim 3, wherein said granules have an average particlediameter of about 2 to about 5 mm.
 5. The process of claim 2, whereinsaid molten flowable mass has a temperature of about 115° C. to about130° C.
 6. The process of claim 1, wherein said extruding includes:providing first and second wall members each having orifices, whereinthe wall members are movable relative to one another to periodicallyalign orifices in the first member with those in the second member forthe predetermined period of time; providing the molten flowable massunder pressure against the first wall member such that when the orificesin the first and second wall members are aligned, said discrete portionsare extruded through the aligned orifices; and receiving and coolingsaid discreet portions on a conveyor belt to form said granularsupernucleophilic 4-(secondary or tertiary)aminopyridine catalyst. 7.The process of claim 2, wherein said extruding includes: providing firstand second wall members each having orifices, wherein the wall membersare movable relative to one another to periodically align orifices inthe first member with those in the second member for the predeterminedperiod of time; providing the molten flowable mass under pressureagainst the first wall member such that when the orifices in the firstand second wall members are aligned, said discrete portions are extrudedthrough the aligned orifices; and receiving and cooling said discreetportions on a conveyor belt to form a granular supernucleophilic 4-N,N-dimethylaminopyridine catalyst.
 8. The process of claim 7, whereinsaid granules have an average particle diameter of about 1 to about 10mm.
 9. The process of claim 8, wherein said granules have an averageparticle diameter of about 2 to about 5 mm.
 10. The process of claim 9,wherein said molten flowable mass has a temperature of about 115° C. toabout 130° C.
 11. A catalyst composition, comprising: a granulatedsupernucleophilic 4-(secondary or tertiary)aminopyridine catalyst. 12.The catalyst composition of claim 11, wherein said catalyst is a4-N,N-dialkylaminopyridine catalyst.
 13. The catalyst composition ofclaim 11, wherein said catalyst is a 4-N,N-dimethylaminopyridinecatalyst.
 14. The catalyst composition of claim 12, which is a prilledcatalyst having prills with an average diameter of about 1 to about 10mm.
 15. The catalyst composition of claim 14, wherein said catalyst is4-N,N-dimethylaminopyridine.
 16. A process for preparing a 4-(secondaryor tertiary)aminopyridine, comprising: reacting a 4-substituted pyridinebase having a leaving group as the 4-substituent, with an activatingagent of the formula:

wherein R³ and R⁴, which may be the same as or may differ from oneanother, are each —H or a C₁-C₄ alkyl group, and Z is —OR⁷or NR⁵R⁶,wherein R⁵ and R⁶, which may be the same as or may differ from oneanother, and may taken together form a ring, are each —H or C₁-C₈ alkyl;and R⁷ is —H or C₁-C₈ alkyl; so as to form a corresponding1,4-substituted pyridine; reacting said 1,4-substituted pyridine with aprimary or secondary amine to substitute an amino group for the leavinggroup at the 4-position, and thereby form a corresponding1-substituted-4-(secondary or tertiary)aminopyridine, wherein said amineis included in a molar ratio of at least about 2:1 relative to the1,4-substituted pyridine and said reacting is conducted in asubstitution reaction medium essentially free from strong base; andtreating the 1-substituted-4-aminopyridine compound to remove the1-substituent and thereby form a product medium including the4-(secondary or tertiary) amino-pyridine.
 17. The process of claim 16wherein the amine is a dialkylamine.
 18. The process of claim 17 whereinthe dialkylamine is dimethylamine.
 19. The process of claim 16, whereinsaid substitution reaction medium at the completion of said reacting hasa pH of about 8 to about
 10. 20. The process of claim 16, wherein saidsubstitution reaction medium has a basic pH essentially as provided bysaid 1,4-substituted pyridine and said amine.
 21. The process of claim20, wherein the amine is dimethylamine.
 22. The process of claim 16,wherein said activating agent is acrylic acid or methacrylic acid. 23.The process of claim 22, wherein said activating agent is acrylic acid.24. The process of claim 23, wherein said activating agent is acrylamideor methacrylamide.
 25. The process of claim 16, also comprising:extracting the 4-aminopyridine compound from product medium into anorganic solvent to form an extracted medium; distilling the extractedmedium to separate the organic solvent from the 4-(secondary ortertiary)aminopyridine.
 26. The process of claim 25, also comprising:after said distilling and without recrystallization of the 4-(secondaryor tertiary)aminopyridine, melt-processing the 4-(secondary ortertiary)aminopyridine to a particulate form.
 27. The process of claim26, wherein the 4-(secondary or tertiary)aminopyridine is a4-N,N-dialkylaminopyridine.
 28. The process of claim 27, wherein the4-dialkylaminopyridine is 4-N,N-dimethylaminopyridine.
 29. The processof claim 28, wherein the melt-processing comprises flaking.
 30. Theprocess of claim 28, wherein the melt-processing comprises extrusiongranulating.
 31. A process for preparing a 4-substituted pyridinecompound, which comprises: first reacting a 4-substituted pyridine basehaving a leaving group as the 4-substituent, with an α-unsaturated ofthe formula

wherein R³ and R⁴, which may be the same as or may differ from oneanother, are each —H or a C₁-C₄ alkyl group; so as to form acorresponding first 1,4-substituted pyridine betaine; second reactingthe 1,4-substituted betaine with a nucleophile to displace the leavinggroup and form a second 1,4-substituted-pyridine betaine; and treatingthe second 1,4-substituted betaine to remove the 1-substituent and formthe 4-substitued pyridine compound.
 32. The process of claim 31, whereinsaid acid is acrylic or methacrylic acid.
 33. The process of claim 32,wherein said acid is acrylic acid.
 34. The process of claim 31, whereinsaid nucleophile is a primary or secondary amine which is present in atleast about a 2:1 molar ratio relative to said first 1,4-substitutedpyridine betaine.
 35. The process of claim 34 wherein the amine is adialkylamine.
 36. The process of claim 35 wherein the dialkylamine isdimethylamine.
 37. The process of claim 35, wherein said second reactingis conducted in a medium essentially free from strong base.
 38. Theprocess of claim 37, wherein said second reacting is conducted at a pHessentially as provided by the amine and the pyridine betaine.
 39. Theprocess of claim 38, wherein the amine is dimethylamine.
 40. The processof claim 31, wherein the 4-substituted pyridine base is 4-cyanopyridine.41. A process for forming a pyridine betaine, comprising: reacting a4-substituted pyridine of the formula:

wherein L is a leaving group selected from cyano, halo, arylsulfonylhaving from six to ten carbon atoms, optionally substituted with one ormore alkyl groups having from one to four carbon atoms; arylsulfonyloxyhaving from six to ten carbon atoms; alkylsulfonyloxy having from one toeight carbon atoms; aryloxy having from six to ten carbon atoms;arylthio having from six to ten carbon atoms; and nitro; with anα,β-unsaturated acid of the formula:

wherein R³ and R⁴, which may be the same as or may differ from oneanother, are each —H or a C₁-C₄ alkyl group, so as to form a1,4-substituted pyridine betaine of the formula:

wherein L, R³ and R⁴ are as defined above.
 42. The process of claim 41,wherein L is cyano.
 43. The process of claim 41, wherein R³ is —H and R⁴is —H or methyl.
 44. The process of claim 42, wherein R³ —H and R⁴ is —Hor methyl.
 45. The process of claim 44, wherein R⁴ is —H.
 46. A pyridinebetaine compound of the formula

wherein: G is a group selected from —CN and —NR¹R², wherein R¹ and R²,which may be the same or may differ from one another, are each —H or ahydrocarbon group having from one to about ten carbon atoms; and R³ andR⁴, which may be the same as or may differ from one another, areselected from —H and C₁-C₄ alkyl groups.
 47. The compound of claim 46,wherein G is —CN.
 48. The compound of claim 47, wherein R³ and R⁴ areeach —H.
 49. The compound of claim 46, wherein G is —NR¹R² .
 50. Thecompound of claim 49, wherein R³ and R⁴ are each —H and R¹and R² areeach methyl.
 51. A process of any of claims 16-45, which is conducted ina continuous fashion.
 52. The process or claim 51, wherein the processis conducted in one or more tube reactors.
 53. A heat stable4-(secondary or tertiary)aminopyridine catalyst which has an APHA colorof less than about 50 and exhibits an increase in APHA color of nogreater than about 50 when heated in a nitrogen atmosphere at about 120°C. for about 24 hours.
 54. The catalyst of claim 53 which is4-N,N-dimethylaminopyridine.
 55. The catalyst of claim 54, which has anAPHA color of less than about 10, and exhibits an APHA color of nogreater than about 50 after heating in a nitrogen atmosphere at about120° C. for about 24 hours.
 56. An amorphous 4-(secondary ortertiary)aminopyridine catalyst having an APHA color of less than 20.57. The catalyst of claim 56 which is 4-N,N-dimethylaminopyridine. 58.The catalyst of claim 57, having an APHA color of less than 10.